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ABSTRACT: Research in the area of simutaneously targeting more than one G protein-coupled receptor (GPCR) has increased in recent times. By exploiting the cross talk between the beta2-adrenergic (beta2AR) and adenosine A1 receptors (A1AR) on adenylate cyclase activity, we synthesized a series of bivalent agonists for both GPCRs to generate responses from more than one receptor. We have demonstrated a relationship between the various beta2-adrenergic and A1 adenosine bivalent parameters of linker and bifunctionality by using data that are drawn from in vitro assays. The hexyl-linked 12e (K(i), 311 nM) and butyl-linked 12c ( K(i), 863 nM) bivalent compounds displayed reasonable binding affinities for the beta2AR when compared with the control (-)isoproterenol (K(i), 136 nM), and both compounds also exhibited a persuasive bifunctional trend for both receptors at various drug concentrations. The bivalent compound 12e was also found to have significant EC50 potency (6 nM) at the beta2AR in DDT cells.
Journal of Medicinal Chemistry 10/2008; 51(19):6128-37. · 4.80 Impact Factor
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Annelies Goeminne,
Maya Berg, Michael McNaughton,
Gunther Bal,
Georgiana Surpateanu,
Pieter Van der Veken,
Stijn De Prol,
Wim Versées,
Jan Steyaert,
Achiel Haemers,
Koen Augustyns
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ABSTRACT: A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important.
Bioorganic & medicinal chemistry 07/2008; 16(14):6752-63. · 2.82 Impact Factor
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ABSTRACT: Thioredoxin (Trx) expression is increased in several human primary cancers associated with aggressive tumor growth and decreased patient survival, and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Various gold(III) compounds with none, one, two or three carbon-gold bonds were evaluated for their capacity to inhibit TrxR and the growth of MCF-7 cancer cells in vitro. Compounds with up to two carbon-gold bonds were often potent inhibitors of TrxR with IC50 values as low as 2 nmol/l. In the presence of Trx and insulin the inhibiting capacity was much lower. However, the inhibitory concentrations of the compounds did not correlate with the ability to kill cells. Out of the organometallics tested, only compound 8 with two carbon-gold bonds was able to inhibit colony formation by MCF-7 breast cancer cells at low micromolar concentrations (IC50=1.6 micromol/l). Unfortunately, the compound did not show any anti-tumor activity against MCF-7 breast cancer and HT-29 colon cancer xenografts in scid mice.
Anti-Cancer Drugs 07/2006; 17(5):539-44. · 2.41 Impact Factor
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ABSTRACT: In enzymatic depurination of nucleosides, the 5'-OH group of the ribose moiety of the substrate is often shown to contribute substantially to catalysis. The purine-specific nucleoside hydrolase from Trypanosoma vivax (TvNH) fixes the 5'-OH group in a gauche,trans orientation about the C4'-C5' bond, enabling the 5'-oxygen to accept an intramolecular hydrogen bond from the C8-atom of the purine leaving group. High level ab initio quantum chemical calculations indicate that this interaction promotes protonation of the purine at N7. Steady state kinetics comprising engineered substrates confirm that a considerable fraction of the catalytic 5'-OH effect can be attributed to leaving group activation.
Journal of Biological Chemistry 05/2005; 280(15):14799-802. · 4.77 Impact Factor
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ABSTRACT: Water-soluble diorganyl tellurides of the alkyl aryl or dialkyl type were prepared by treatment of mono-6-tosyl-beta-cyclodextrin with sodium alkanetellurolates or arenetellurolates or sodium telluride. The novel cyclodextrin-derived organotelluriums were evaluated for their capacity to catalyze the reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione, NADPH, and GSSG-reductase (coupled reductase assay). Cyclodextrins 4d and 4e, carrying 4-(N,N-dimethylamino)phenyltelluro and n-butyltelluro groups, respectively, were the most efficient glutathione peroxidase mimics. Reduction of lipophilic cumene hydroperoxide often proceeded 10-20 times faster than reduction of the more hydrophilic hydroperoxides, which cannot bind into the hydrophobic interior of the cyclodextrin. Thus, it seems that the carbohydrate moiety acts as a binding site for the hydroperoxide substrate. The cyclodextrin derivatives were also evaluated for their capacity to inhibit thioredoxin reductase/thioredoxin and cancer cell growth in culture. IC(50) values for inhibition of thioredoxin or thioredoxin/thioredoxin reductase were in the submicromolar range for the best inhibitors (compounds 4d and 5). Two of the compounds (4c and 5) were found to inhibit the growth of MCF-7 cells in culture with IC(50) values in the low micromolar range.
Journal of Medicinal Chemistry 02/2004; 47(1):233-9. · 5.25 Impact Factor
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ABSTRACT: The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.
Bioorganic & Medicinal Chemistry 12/2003; 11(23):5091-100. · 2.92 Impact Factor
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ABSTRACT: Thioredoxin (Trx) expression is increased in several human primary cancers and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Novel organotellurium antioxidants, especially a primitive analog of vitamin E (compound 1d) and compounds 7, 9 and 10--all carrying highly functionalized 4-(dialkylamino)phenyltelluro groups to secure high antioxidative capacity--were found to inhibit TrxR with IC50 values in the low micromolar range. Whereas antioxidant 1d also inhibited the growth of MCF-7 human breast cancer cells in culture at a similar level (IC50 = 1.8 microM), the other TrxR inhibitors were inactive in concentrations below about 10 M.
Anti-Cancer Drugs 03/2003; 14(2):153-61. · 2.41 Impact Factor
